Trends in Biochemical Sciences
ReviewFeature ReviewThe histone shuffle: histone chaperones in an energetic dance
Section snippets
Histone chaperones
The nucleosome hypothesis for chromatin, proposed by Don and Ada Olins and Roger Kornberg in 1974 1, 2, was a paradigm shift for research into eukaryotic genomic processes. We now know that chromatin comprises a repeated array of nucleosome core particles of approximately 147 bp DNA wound 1.7 times around the outside of a core histone octamer which includes two molecules each of histone proteins H2A, H2B, H3 and H4 (Box 1) separated by varying lengths of linker DNA which can be associated with
The need for histone chaperones
From an energetic standpoint, arguably the largest transitions in chromatin dynamics occur during the processes of assembling and disassembling nucleosomes, and not surprisingly, the assembly and disassembly of nucleosomes occurs in a stepwise fashion. It has been generally accepted that some form(s) of the pathway illustrated in Figure 1 operates to construct nucleosomes from component histone dimer precursors (Box 1). The pathway includes the assembly of H3–H4 dimers into H3–H4 tetramers, a
Structural forms of histone chaperones
Histone chaperones are as varied as the processes they promote. Many specialized chaperones for the histones that form the nucleosome core particle (core histones) and those that interact with the nucleosome core and the linker DNA (linker histones) participate at each step in the processes of nucleosome assembly, disassembly and histone exchange during different genomic processes (Table 1) 11, 14. Additionally, specific variant histone chaperones, such as yeast Chz1 and Yaf9, recruit H2AZ,
Implications of oligomeric status of histone chaperones and the surfaces of the histones to which they bind
Several themes have emerged from detailed analyses of histone chaperones. They have different oligomeric states that correlate with their roles in different stages of nucleosome assembly. Moreover, they show a variety of multimeric interactions that involve different regions of the chaperones and different regions of the histones (Table 2). There are generally two types of histone chaperone–histone binding: simple 1:1 or 2:2 with affinity values in the range of 1–100 nM and multimeric histone
The nucleosome assembly process
Multiple steps, in parallel pathways, lead to the formation of the ultimate product of chromatin assembly – the nucleosome core particle (Figure 3). The incorporation of specific histone post-translational modifications and the hand-off or ‘shuffle’ of the histones between histone chaperones are common themes along these pathways. Histones H2A–H2B and H3–H4 are delivered via distinct pathways that usually utilize distinct histone chaperones, coming together only on the DNA.
Arguably the earliest
Disassembly of nucleosomes
Chromatin disassembly appears to be the stepwise opposite of the assembly process with one major difference [42] being that nucleosome disassembly is an intrinsically energetically unfavorable process. The requirement for ATP-dependent chromatin remodeling complexes for chromatin disassembly is understandable [42], given the need to break the histone–DNA contacts to allow removal of the histones by the histone chaperones. Although the basic steps and players are beginning to be uncovered, there
Histone chaperone-guided folding pathways
The histone hand-off during assembly must be energetically favorable. Although it is convenient to think of nucleosome assembly as a stepwise process (Figure 1), highlighting the central role that chaperones play in the pathway, the ‘nucleosome assembly funnel’ (Figure 4) provides a thermodynamic perspective to the process. In this view, which is analogous to the protein folding problem, histone chaperones perform functions similar to those of protein folding chaperones in guiding the folding
Concluding remarks
Histone chaperones are key players involved in maintaining histone stability and dynamics in the cell. Structural, biophysical and biochemical information on histone chaperones is beginning to shape a new understanding of the integrated mechanisms of action for this important family of proteins (Box 2). The varied structural motifs and oligomeric states drive electrostatic and conformation-specific interactions between histone chaperones and different faces of the histones, resulting in a
Acknowledgments
Owing to limitations on the number of references, we were unable to directly cite all of the relevant literature, and many relevant references can be found within the cited references. We are grateful to members of the Churchill and Tyler labs for their suggestions for the manuscript. We are especially grateful to Siddhartha Roy for assistance with the figures. We acknowledge support from NIH GM and NCI to J.K.T., NIH GM to M.E.A.C. and a Susan Komen Fellowship to C.D.
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